For the past century, various chemical entities have been used to lower intraocular pressure in an attempt to prevent progressive vision loss in patients with glaucoma or other forms of ocular hypertension. Drugs that are currently employed in the therapy of glaucoma can be pharmacologically classified into the following groups: (a) direct and indirect parasympathomimetics (e.g. pilocarpine and echothiophate); (b) adrenergic agonists (e.g. epinephrine); (c) .beta. and .alpha.-adrenergic antagonists (e.g. timolol and thymoxamine); (d) carbonic anhydrase inhibitors (e.g. acetazolamide); and, (e) hyperosmotic agents (e.g. glycerol). Although these drugs are effective in lowering intraocular pressure in a majority of glaucoma patients, they can cause distressing, and sometimes intolerable, side effects such as: (i) miosis, ciliary muscle spasm, retinal detachment and cataracts (by cholinergics); (ii) reactive hyperemia, burning and adrenochrome pigmentation (by adrenergic agonists); (iii) allergic reactions, burning and conjunctional hyperemia (by adrenergic antagonists); and, (iv) serum electrolyte imbalances and renal calculi (by carbonic anhydrase inhibitors). Furthermore, these drugs and hyperosmotic agents can cause significant systemic toxicity.
In the search for new and better antiglaucoma medications, several additional miscellaneous agents are currently being investigated. Among these are reduced benzoquinolines, isoproterenol, forskolin, cholera toxin, terbutaline, salbutamol, pirbuterol, vanadate, nylidrin, cannabinoids, prostaglandins, valinomycin, atriopeptins, neuropeptide Y, antazoline, ethacrynic acid, spironolactone, tetrahydrocortisol, angiotensin converting enzyme inhibitors, organic nitrates, melatonin, calcium channel blockers, tetracycline derivatives and haloperidol (M. B. Shields, In Textbook of Glaucoma, Third Edition, Williams & Wilkins, Baltimore, pp. 446-521, 1992). These compositions have been shown to be effective in lowering intraocular pressure in concentrations ranging from 0.001 to 10.0 percent.
The bicyclic hexahydroaporphines and 1-p-substituted benzyloctahydroisoquinolines described in this application are structurally distinct from any of the molecules currently available on the pharmaceuticals market or under clinical investigation. In addition, the highly lipophilic nature of these structures allows for effective penetration after topical administration in the eye. They represent a new class of potential antiglaucoma agents which may provide a safe and convenient route to the control of ocular hypertension.
The tetracyclic molecule known commonly as apomorphine (FIG. 2) is a well recognized non-selective agonist at dopamine receptors. The A-ring reduced analog (10-hydroxy-N-methyl-1,2,3,3a,11b, 11c-hexahydroaporphine, FIG. 2) has been generated by many as a byproduct of the Grewe synthesis of the tetracyclic morphinan opioid levorphanol (FIG. 2) but, to date, no therapeutic utility has been elucidated for hexahydroaporphinic molecules. The bicyclic N-formylhexahydroaporphine 1 (FIG. 3) was generated in theoretical yield during an attempt to produce a bicyclic analog of levorphanol through the reaction of the precursor bicyclic N-formyl-1-p-methoxybenzyloctahydroisoquinoline (8, FIG. 3) with anhydrous hydrofluoric acid. The additional bicyclic hexahydroaporphine and 1-p-substituted benzyloctahydroisoquinoline molecules shown in FIG. 3 were generated from the N-formyl analog, 8 through additional reductive or hydrolytic and substitution reactions.